Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: FUNCTIONS OF ANGIOTENSIN PEPTIDES IN THE ROSTRAL VENTROLATERAL MEDULLA

• 1 It was first shown several years ago that the rostral part of the ventrolateral medulla (VLM) contains a high density of receptor binding sites for angiotensin II (AngII). In the present paper we briefly review recent studies aimed at determining the actions of both exogenous and endogenous angiotensin peptides in the rostral VLM, as well as their specific sites of action.
• 2 The results of these studies have shown that angiotensin peptides can excite pressor and sympathoexcitatory neurons in the rostral VLM, but do not appear to affect non-cardiovascular neurons in this region.
• 3 It is known that pressor neurons in the rostral VLM include both catecholamine and non-catecholamine neurons. There is evidence that, at least in conscious rabbits, both of these types of neurons are activated by AngII. The specific endogenous angiotensin peptide or peptides that affect pressor neurons in the rostral VLM have not yet been definitively identified.
• 4 It is also possible that different angiotensin peptides may have different effects on pressor neurons in the rostral VLM, mediated by different receptors. Further studies will be needed to define these different functions as well as the specific receptors and cellular mechanisms that subserve them.

     

Functions of angiotensin peptides in the rostral ventrolateral medulla

1. It was first shown several years ago that the rostral part of the ventrolateral medulla (VLM) contains a high density of receptor binding sites for angiotensin II (AngII). In the present paper we briefly review recent studies aimed at determining the actions of both exogenous and endogenous angiotensin peptides in the rostral VLM, as well as their specific sites of action. 2. The results of these studies have shown that angiotensin peptides can excite pressor and sympathoexcitatory neurons in the rostral VLM, but do not appear to affect non-cardiovascular neurons in this region. 3. It is known that pressor neurons in the rostral VLM include both catecholamine and non-catecholamine neurons. There is evidence that, at least in conscious rabbits, both of these types of neurons are activated by AngII. The specific endogenous angiotensin peptide or peptides that affect pressor neurons in the rostral VLM have not yet been definitively identified. 4. It is also possible that different angiotensin peptides may have different effects on pressor neurons in the rostral VLM, mediated by different receptors. Further studies will be needed to define these different functions as well as the specific receptors and cellular mechanisms that subserve them.     

Male contraception today

The current and potential role of males in family planning is often underestimated. The use of female contraceptive methods tends to require more outside assistance than the use of male methods; therefore, the role of males is less visible and harder to document. Furthermore, males often exert considerable influence over their wives' contraceptive choices but this influence is exerted in the privacy of the home rather than in clinical settings. The value of condoms and of male sterilization procedures is also underrated. The condom is effective, is not associated with negative side effects, and is easy to distribute and to use. In addition, it provides protection from sexually transmitted diseases. Its use should be encouraged. Vasectomies, compared to female sterilization procedures, are simpler to perform and are associated with fewer complications. Efforts to simplify vasectomies even further are also being made. Investigators are currently attempting to occlude the vas by injecting a mixture of alcohol and formaldehyde through the skin. Other investigators continue their efforts to develop a male contraceptive pill; however, since males produce new sperm throughout their reproductive life span, it is more difficult to induce infertility in men than in women. The use of drugs to inhibit sperm production may also induce sperm maturations. Clinical trials of alpha chlorhydrin, which interferes with the sperm maturation process have been conducted, and in 1978 the Chinese began to use gossypol to suppress sperm production. Most of the male contraceptive agents currently being investigated offer little promise and it may be at least 10 years before an effective male pill is produced.     

Wider opportunities for IUD insertion

The timing of IUD insertion has important implications for those who insert the devices as well as the users. In 1978 the US Food and Drug Administration recommended insertion during menstruation but acknowledged that it is also "necessary and proper" to insert IUDs at other times in the cycle. A 1977 study found that 30% of European and North American obstetricians limited insertion to the time of menstruation. Nearly half those in Africa and the Middle East and 13% of those in Asia followed this practice. Consequently, many women are required to make more than 1 visit to a clinic, meaning inconvenience for both the user and provider and some unintended pregnancies. In developing countries women may depend on mobile clinics or infrequent visits by trained personnel and many seek help without an appointment. 1 reason for insertion at or just after menstruation is to ensure that the woman is not pregnant when the IUD is inserted. 2 recent articles attempt to assess the best time for IUD insertion with regard to IUD performance. White et al. found that women whose Copper T IUDs were inserted on days 1-5 of the menstrual cycle had a lower continuation rate in the 1st few months than did those whose IUDs were inserted at a later time in the cycle. Edelman et al. found that Copper T and Copper 7 IUDs could be inserted at any time during the menstrual cycle without any increased risk of subsequent pregnancy, removal for medical reasons or expulsion during the 1st 12 months after insertion. Pooled International Fertility Research Program (IFRP) data indicate that there is no consistent pattern with regard to the time in the cycle that the IUD is inserted and its later performance. In no case is there a distinct advantage for the 1st 5 days of the menstrual cycle. It is much simpler to offer a woman an IUD when she is first seen, provided she is reasonably sure she is not pregnant. New practices are evolving in relation to recently pregnant women. The postabortal use of IUDs has been extensively researched and is a useful option, using a variety of currently available devices. In regard to the postpartum use of IUDs, some programs have reported a high expulsion rate. Provided proper insertion technique is used, IUDs can be inserted immediately postpartum with a high degree of retention. Another use for copper containing IUDs is insertion within 5 days of unprotected sexual intercourse. In sum, women can be provided with IUDs upon request at any time during the menstrual cycle.     

Bacteriologic and endotoxin analysis of salvaged blood used in autologous transfusions during cardiac operations.

Autologous blood transfusion is a common method of reducing the need for heterologous blood transfusion during cardiac operations. Recently we investigated an outbreak of severe, nonsurgical postoperative bleeding among patients undergoing heart operations and receiving intraoperative transfusion of blood from a cell conservation device (Cell Saver System, Haemonetics Corp., Braintree, Mass.). As a result of this investigation, we conducted a prospective study to determine if bacterial or endotoxin contamination of the blood collected in the Cell Saver System and used for reinfusion during heart operations contributes to postoperative bleeding complications. Patients' blood samples were collected immediately before operation, at the end of cardiopulmonary bypass, 1 hour postoperatively, and from the Cell Saver System. All blood samples were cultured for bacteria, and all plasma samples were assayed for endotoxin. Preoperatively all patients having heart operations were without signs of infection, 33 of 37 blood cultures taken were negative, and none of the plasma samples had detectable endotoxin. After discontinuance of cardiopulmonary bypass but before delivery of blood from the Cell Saver System, bacteria and endotoxin were detected in 11 of 36 (30.6%) and five of 35 (14.3%) of the patients' blood samples, respectively. The blood aspirated from the open chest and collected by the Cell Saver System was culture positive in 30 of 31 (96.8%) samples, and seven of 29 (24.1%) contained endotoxin. One of 28 blood samples collected 1 hour postoperatively was culture positive, and five of 25 samples contained endotoxin. Of 61 total microorganisms isolated, 50 (82%) were coagulase-negative staphylococci, four (6.6%) aerobic diphtheroids, five (8.2%) anaerobic "diphtheroids" (Propionibacterium acnes), and two (3.2%) gram-negative bacilli. Plasma endotoxin concentrations ranged from 10 to 765 pg/ml. No signs of endotoxemia or unusual bleeding were observed intraoperatively or postoperatively in any of the 38 patients. Although blood collected in the Cell Saver System and used for reinfusion during heart operations often was contaminated with gram-positive bacterial commensals of the skin and low concentrations of endotoxin, no adverse effects were noted in the patients.     

The evolution of ductus arteriosus treatment

The treatment of patent ductus arteriosus (PDA) has evolved over the years. We reviewed 231 non-premature children (group 1) undergoing surgical closure of a PDA between January 1985 and December 1997, and 30 children (group 2) undergoing transcatheter closure from May 1995 to December 1998. The median age and weight at operation in group 1 were 13 months (range, 0.5-174 months) and 9.5 kg (range, 1.9-49.7 kg), respectively. There was one intra-operative death (0.4%) secondary to hemorrhage. Immediate extubation was performed in 208 patients (90%). Intra-operative chest tube use decreased from 73.3% to 10% between the 1985-88 and 1996-97 periods (P < 0.001). Postoperative pneumothoraces occurred in 33/131 (25%) patients with only one patient (0.7%) requiring drainage. Eleven patients had complications including wound infection in four, vocal cord paralysis in three, and left pulmonary artery stenosis in one. The median length of stay (LOS) was 5 days (range, 2-43 days). Follow-up echocardiogram was performed in 146/230 patients (63%) and revealed a residual PDA in six (4%); two being re-ligated, two remaining clinically insignificant, and two spontaneously resolved at 7 and 28 months follow-up. The remaining 84 patients had no clinical signs of a residual PDA. In group 2, where a transcatheter coil occlusion technique was used, the median age and weight at procedure were 31 months (range, 9-320 months) and 14.9 kg (range, 9-69.7 kg), respectively. Vascular complications occurred in four patients (13.3%). One patient developed hemolysis and hemoglobinuria requiring hospital admission. Four patients required a second intervention. At the most recent echocardiographic assessment, four patients (13.3%) had a residual PDA.     

Clearance of atrial natriuretic factor by lung, liver, and kidney in human subjects and the dog.

We determined human and canine plasma clearance of atrial natriuretic factor (ANF) by lung, liver, and kidney from arteriovenous differences in plasma ANF and measured organ plasma flow. Human subjects had lower plasma ANF concentrations in the pulmonary vein or the pulmonary capillary wedge position when compared with the pulmonary artery, and both sites yielded pulmonary ANF extraction ratios of 24%. Canine lung ANF extraction was 19 +/- 3% and pulmonary ANF clearance was 328 +/- 78 ml/min per m2 vs. 357 +/- 53 ml/min per m2 in man. Hepatic plasma ANF clearance was 216 +/- 26 ml/min with an extraction ratio of 30 +/- 3% in humans and 199 +/- 89 ml/min and 36 +/- 6% in the dog. Renal plasma ANF clearance in human subjects was 78 +/- 12 ml/min per kidney and correlated well with each kidney's creatinine clearance (r = 0.58, P less than 0.05). The mean renal ANF extraction ratio was 35 +/- 4% in human subjects and 42 +/- 6% in the dog. These data quantitate the specific organ ANF clearances by lung, liver, and kidney in human subjects and in dogs and provide a rationale for elevated plasma ANF levels in cirrhosis, renal failure, and diseases accompanied by reduced perfusion of these organs. These findings support the conclusion that plasma ANF concentrations are dependent upon both the stimuli for ANF secretion as well as the specific organ clearances of ANF.     

Discrimination of MHC-derived odors by untrained mice is consistent with divergence in peptide-binding region residues

Genes of the major histocompatibility complex (MHC) play a central role in immune recognition, yet they also influence the odor of individuals. Mice can be trained to distinguish odors mediated by classical MHC loci; however, training can introduce confounding behavioral artifacts. This study demonstrates that mice can distinguish some, but not all, naturally occurring allelic variants at classical MHC loci without prior training. This result suggests that MHC-disassortative mating preferences might operate by means of small MHC-based odor differences, and could therefore contribute to diversifying selection acting on MHC loci. Here we show that odors of two MHC mutant mouse strains (bm1 and bm3) can be distinguished, even after genetic background is controlled by intercrossing strains. These two strains differ by five amino acids, three of which are predicted to chemically contact peptides bound to the peptide-binding region (PBR), the site of antigen presentation for T cell recognition. However, the odors of neither bm1 nor bm3 were distinguished from their parental B6 haplotype after randomizing genomic background, despite discrimination of pure-bred B6 and bm1 strain odors. These combined results suggest that (i) there may be an MHC odor discrimination threshold based on divergence in PBR residues, providing a more logical pattern of MHC-based odor discrimination than found in previous training studies, where discrimination ability was not correlated with PBR divergence; and (ii) additional (non-MHC) mutations that influence odor have accumulated in these strains during the 100 generations of divergence between pure B6 and bm1 strains.